The immune system protects individuals from infective agents, e.g., viruses, bacteria, multi-cellular organisms, and cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. Immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Cytokines have been implicated in immune response to a number of viral infections (see, e.g., Abbas, et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; Kaufmann, et al. (2001) Immunobiol. 204: 603-613; Saurez and Schultz-Cheery (2000) Dev. Comp. Immunol. 24: 269-283; van Reeth and Nauwynck (2000) Vet. Res. 31: 187-213; Garcia-Sastre (2001) Virology 279: 375-384; Katze, et al. (2002) Nat. Rev. Immunol. 2: 675-687; van Reeth (2000) Vet. Microbiol. 74: 109-116; Tripp (2003) Curr. Pharm. Des. 9: 51-59).
Influenza virus is a leading viral cause of mortality, contributing to 20,000 deaths in the United States per year. The virus destroys the airway epithelium and can spread to extrapulmonary tissues. High risk individuals include those over the age of 65 years, and those with disorders such as chronic obstructive pulmonary disease (COPD), asthma, chronic heart disease, diabetes, chronic renal or hepatic disease, cancer, or chronic connective tissue disease. Influenza viruses are classified in three types, A, B, and C, of which A is clinically the most important. The genome of the influenza A virus encodes ten proteins. Due to the antigenic variability on the surface proteins, e.g., hemagglutinin and neuramimidase, it has not been possible to produce a vaccine that provides long lasting protection for, e.g., the influenza A virus (IV) strain (see, e.g., Treanor (2004) New Engl. J. Med. 350: 218-220; Steinhauer and Skehel (2002) Annu. Rev. Genet. 36: 305-332; Mozdzanowska, et al. (2000) J. Immunol. 164: 2635-2643; Nicholson, et al. (2003) The Lancet 362: 1733-1745).
With influenza infection, virus specific CD8+ T cells occur at elevated concentrations in the respiratory tract, and rapidly express effector functions upon re-exposure to viral antigen. Although influenza virus replication is essentially limited to the respiratory tract, the infection results in activation of immune cells in the respiratory tract, but also elsewhere in the body, e.g., liver. CD8+ T cells combat virus infection through direct lysis of infected cells or by secretion of antiviral cytokines, such as interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha). IFNgamma induces proteins that inhibit viral replication, e.g., through impairing metabolism of viral mRNA and double stranded RNA. Moreover, IFNgamma activates antigen presenting cells (APCs), e.g., by upregulating major histocompatiblity complex (MHC) on the APCs.
Immune response to primary and secondary infection with influenza has different properties, as IFNgamma appears not needed for response to primary infection, but is used for recovery from secondary infection. Another difference is that CD8+ T cell response to acute infections, e.g., early stages of acute viral infection, is relatively independent of CD4+ T cells, whereas response by memory CD8+ T cells in secondary infections, is enhanced by CD4+ T cells. After primary infection with influenza, large pools of memory CD8+ T cells persist in secondary lymph organs, as well as in non-lymphoid tissues, such as lungs and liver (see, e.g., Kaech and Ahmed (2003) Science 300: 263-265; Sun and Bevan (2003) Science 300: 339-342; Turner, et al. (2003) Immunity 18: 549-559; Ely, et al. (2003) J. Immunol. 170: 1423-1429; Topham, et al. (2001) J. Immunol. 167: 6983-6990).
Further differences between response to primary and secondary viral infections are as follows. Viral peptides bound to MHC Class I molecules stimulate CD8 T cells, where the characteristics of CD8′ T cell response, e.g., cytokine production, can differ, depending on the identity of the peptide that is presented and whether the viral infection is primary or secondary. For example, primary infection can involve immune response by T cells specific for influenza nucleoprotein and for influenza acidic polymerase, but during secondary infection, most of the T cells recognize nucleoprotein but not acidic polymerase. After primary exposure, about 12% of CD8′ T cells taken from lungs is specific for the NP366-374 epitope, while after secondary exposure this figure increases, e.g., to 60-70%. Changes in immune response during primary or secondary infection can reflect changes in the identity of the APC that presents antigen, e.g., a dendritic cell (DC) versus a macrophage, and on differences in the DC's ability versus macrophage's ability to activate a memory T cell during secondary infection (see, e.g., Yewdell and Garcia-Sastre (2002) Curr. Opin. Microbiol. 5:414-418; Stiver (2003) Canadian Medical Assoc. J. 168:49-57; Nguyen, et al. (2000) J. Virol. 74:5495-5501; Graham, et al. (1993) J. Exp. Med. 178:1725-1732; Wong and Pamer (2003) Annu. Rev. Immunol. 21:29-70; Crowe, et al. (2003) J. Exp. Med. 198:399-410; Julkunen, et al. (2001) Vaccine 19:S32-S37; Webby, et al. (2003) Proc. Natl. Acad. Sci. USA 100:7235-7240; Turner, et al., supra; Wiley, et al. (2001) J. Immunol. 167:3293-3299; Belz, et al. (2000) J. Virol. 74:3486-3493; Belz, et al. (1998) Proc. Natl. Acad. Sci. USA 95:13812-13817).
Long lasting and broad immunity against influenza may depend on the ability to generate CD8+ T cell responses, but generation of this response is often not effective with the current vaccines. There is an unmet need to provide protection against viruses during primary and secondary immune responses, e.g., to influenza virus. The present invention fulfils this need by providing methods of using agonists and antagonists of IL-23 and IL-23 receptor.